PD-1 and PD-L1 expression in Multiple Myeloma patients

Multiple myeloma is an incurable plasma cell malignancy with only 30% of patients surviving for more than 10 years. The bone marrow microenvironment is crucial to the survival, proliferation and growth of these malignant plasma cells and has also been heavily implicated in drug resistance. Therefore, therapeutic targeting of the microenvironment has gained interest in conjunction with targeting myeloma cells themselves. Multiple myeloma is an extraordinarily complex hematological disease in regards to its ability to manipulate the cells in the bone marrow microenvironment, as well as its genesis and progression. Multiple myeloma is a malignancy that is heavily associated to relapse after therapy. The strong dependence malignant plasma cells have on the bone marrow microenvironment makes it extremely difficult to effectively treat this disease, with a small residual population of drug-resistant myeloma cells remaining within the bone marrow after nearly all cases of treatment. An important achievement in the immunotherapeutic treatment of cancer was the discovery of the PD-1/PD-L1 pathway, its function in the evasion of tumor immunity, and the development of targeted antibodies. The PD-1 pathway has been shown to be extraordinarily successful in slowing or clearing tumors in multiple human cancers. Although no definitive biomarker to predict success of PD-1 immunotherapy has been described, the pre-treatment density of CD8+ T cell infiltration and expression of PD-1 or PD-L1 in the tumor microenvironment all correlate with responsiveness to PD-1 targeted therapies. Memory T cells likely play an important role in the response to tumor recurrence and metastases. Blocking PD-L1 may be a more effective therapeutic strategy than blocking PD-1, and that blocking both PD-1 and PD-L1 may be an effective combination. Although the majority of clinical effort has been put towards antibodies blocking PD-1, an antibody blocking PD-L1 interactions with both PD-1 and B7-1 has been approved in non-small cell lung cancer and bladder cancer. Anti- PD-1/PD-L1 antibody treatment could be clinically effective in MM patients by recovering T-cell cytotoxicity and inhibiting reverse signaling from PD-L1 on MM cells. Therefore, the use of combination therapies may significantly improve the impact of checkpoint inhibition as a treatment modality for selected patients. Flow cytometry may be a reliable, easy and value effective tool for the assessment of minimal residual disease in patients with multiple myeloma. Longer remissions that cannot be accurately evaluated with conventional techniques, such as immunofixation and electrophoresis, are achieved by novel drugs, which dramatically enhance patients' outcomes. Understanding the distribution of PD-1/PD-L1 molecules within the bone marrow niche of patients with multiple myeloma and the contribution of immune resistance mechanisms to PD-1/PD-L1 blockade represents a critical step in order to identify the best patient subset that could benefit from this check-point blockade and to provide rationale for new combined therapeutic strategies.